In general, (S)-indoline-2-carboxylic acid and methyl ester compounds thereof are currently used as an intermediate of many novel medicines in experimental and clinic steps, and as well, may be applied as an intermediate of a therapeutic agent for the treatment of hypertension, such as Perindopril™, which is presently commercially available from Servier (France), when being converted to (2S)-(2α,3αβ, 7αβ)-octahydroindole-2-carboxylic acid through hydrogenation. Thus, intensive researches on (S)-indoline-2-carboxylic acid and (S)-indoline-2-carboxylic acid methyl ester have been performed.
At present, the production of optically active (S)-indoline-2-carboxylic acid and methyl ester thereof is largely classified into four methods, that is, (1) recrystallization using a chiral auxiliary, (2) asymmetrical hydrogenation using a chiral auxiliary, (3) chemical synthesis through asymmetrical reduction using a chiral auxiliary, and (4) enantioselective hydrolysis using a microorganism and an enzyme.
First, the recrystallization method is characterized in that an optically active compound is used as an auxiliary, and thus a certain optical isomer is selectively pre-cipitated as a salt and separated from the other optical isomer. In this regard, (+)-alpha-methylbenzylamine is used as the chiral auxiliary to separate only (S)-indoline-2-carboxylic acid having optical purity of 96% e.e. (Vincent M. et al., Tetrahedron Letters, 23(16), 1677, 1982).
In addition, (−)-(R,R)-4-(O2N)C6H4CH(OH)CH(NH2)CH2OH is utilized as the chiral auxiliary, along with acetylated indoline-2-carboxylic acid, thereby separating only the acetylated (S)-indoline-2-carboxylic acid with an optical purity of 99% e.e. (Hendrickx A. J. J. & Kuilman T., EP 937,714 (1999)). However, the recrystallization method is disadvantageous in that the used chiral auxiliary is expensive and also is difficult to recover, thus negating economic benefits. Thus, it is difficult to apply the above method to commercial industries.
Second, the asymmetrical hydrogenation method using the chiral auxiliary is characterized in that a substrate and a metal catalyst having a chiral ligand are added to a solvent, followed by optically selective hydrogenation of the substrate. For example, acetylated indoline-2-carboxylic acid methyl ester is hydrogenated, together with [Rh(norbomadiene)2]+SbF6− as the catalyst, and bis(diphenylphosphinoethyl)-biferrocene(S,S)-(R,R)-PhTRAP as the ligand, in an isopropanol solution containing cesium carbonate, under the conditions of 60° C. and 5.0 Mpa, to produce acetylated (S)-indoline-2-carboxylic acid methyl ester with an optical purity of 95% e.e., as the yield of 95% (Kuwano R. et al., JACS, 122(31), 7614, 2000). The above method is advantageous in terms of high yield of the product, but suffers from drawbacks, such as low optical purity, and the use of expensive chiral auxiliary for the hydrogenation, in which the chiral auxiliary is difficult to synthesize. Further, since the above hydrogenation method requires expensive equipments and facilities, it cannot be employed for a large-scaled process.
Third, the chemical synthesis method through the asymmetrical reduction using the chiral auxiliary is characterized by optically selective reduction of a pro-chiral type nitrophenyl pyruvic acid by use of the chiral auxiliary, to prepare an alcohol derivative, which is then used as an intermediate to produce optically active (S)-indoline-2-carboxylic acid. In this regard, while D-(+)-Proline and sodium borohydride (NaBH4) are used as the chiral auxiliary and a reducing agent, respectively, nitrophenyl pyruvic acid is subjected to an optically selective reduction, thus synthesizing (S)-alpha-hydroxybenzenepropionic acid with the yield of 85%. Subsequently, the synthesized (S)-alpha-hydroxybenzenepropionic acid is chlorinated, followed by reducing a nitro group to an amine group to make a cyclic structure in a basic aqueous solution, to finally synthesize (S)-indoline-2-carboxylic acid (Buzby G. C. Jr et al., U.S. Pat. No. 4,614,806 (1988)). However, the above method is disadvantageous in that (S)-indoline-2-carboxylic acid is synthesized through many reaction steps, for example, four steps from nitrophenyl pyruvic acid, thus obtaining a very low reaction yield, not more than 32%. Further, the above method is disadvantageous in terms of the use of expensive of D-(+)-proline, and thus it is impossible to produce the target product economically.
Fourth, the enantioselective hydrolysis method using the microorganism and the enzyme includes two type processes proposed separately by Asada et al. and Oreste et al.
By Asada et al., alcohol having a higher molecular weight, selected from the group consisting of butanol, amylalcohol, benzylalcohol, cyclohexanol, cyclohexandiol, glycerol, glycerol-alpha-monochlorohydrine, ethyleneglycol, dichloropropanol, monochlorohydrine, and pentantriol, reacts with racemic indoline-2-carboxylic acid to prepare an ester compound, which is then subjected to an optically selective resolution by use of an industrial enzyme and an enzyme purified from microorganisms, to produce (S)- or (R)-ester compound, which is then further hydrolyzed, concentrated, crystallized, precipitated and filtered, thus finally obtaining (S)- or (R)-indoline-2-carboxylic acid having high optical purity (Asada et al., U.S. Pat. No. 4,898,822 (1990)).
Although the ester compound composed of alcohol having a higher molecular weight, used as the substrate, can increase the yield due to the enhancement of an adsorption ratio to a hydrophobic resin filled in a column, it decreases the number of moles per unit volume in the same amount, compared to ester compounds having a lower molecular weight, thereby lowering the yield of the overall reaction, resulting in increased process costs.
Among the enzymes and microorganisms using by Asada et. al., steapsin and a hydrolytic enzyme derived from Arthrobacter nicotianea have relatively higher activity.
Although steapsin is an inexpensive lipase obtained from the pancreas of pigs, it has only 25% of protein based on total amounts thereof, in which the protein further includes amylase and protease. Thereby, side reactions occur and thus impurities are easily produced. Also, upon separation and purification of the product, since an emulsion layer is formed by impurities and unnecessary proteins in the total proteins of Steapsin, the separation/purification process is difficult to perform, and as well, the purification yield decreases.
Moreover, the enzymes derived from the microoranisms are different in titers and activities according to culture conditions of the microorganisms, and the purification of enzymes requires a complicated process, such as column chromatography. Further, the (S)- or (R)-ester compound obtained from the enzymatic reaction can be converted to (S)- or (R)-indoline-2-carboxylic acid having high optical purity by means of complicated processes, such as hydrolysis, concentration, crystallization, pre-cipitation and filtration. Hence, the reaction process suffers from complexity and the lower yield, thus negating economic benefits.
Meanwhile, by Oreste et al., the racemic acetylated indoline-2-carboxylic acid methyl ester is selectively hydrolyzed by the microorganism and the enzyme to produce the acetylated (S)-indoline-2-carboxylic acid methyl ester having optical activity (Oreste G. et al., DE 3,727,411 (1988)). However, since the resultant acetylated (S)-indoline-2-carboxylic acid methyl ester has the yield of 9% and the optical purity of maximal 98% e.e., the above method cannot be applied for an industrial production process requiring both high optical activity and high yield. Further, because the acetyl group should be removed from the product, the chiral center may be easily racemized, therefore decreasing the optical purity.